Recent progress in tyrosine kinase 2 inhibitors for atopic dermatitis.

INTRODUCTION: Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by persistent itching. Conventional treatments for AD include topical corticosteroids and calcineurin inhibitors, but there are emerging therapies targeting the JAK-TYK2 pathway that are promising for the treatment of AD. AREAS COVERED: This review comprehensively explores the pathogenesis, triggers, clinical manifestations, and conventional treatment options for AD. In addition, we discuss novel therapeutic agents targeting alternative signaling pathways, with a focus on clinical trials evaluating tyrosine kinase 2 (TYK2) inhibitors, including systemic and topical agents. We also provide a detailed assessment of ICP-332 efficacy, safety, and potential adverse effects in moderate-to-severe AD. EXPERT OPINION: Janus kinase inhibitors that have been recently approved have shown promise for the treatment of AD, especially for patients with severe phenotypes. Preliminary findings from randomized controlled trials suggest that TYK2 inhibitors exhibit rapid efficacy and acceptable safety in the management of AD; however, additional investigations, including long-term trials, are warranted to fully understand their efficacy and safety profile.

Prospective Clinical Study: Full-Body Blue Irradiation in the Treatment of Atopic Dermatitis.

INTRODUCTION: Ultraviolet-free (UV-free) blue light phototherapy has emerged as a promising option due to its reported efficacy and minimal adverse effects. This study aims to evaluate the effectiveness of full-body blue light irradiation in both adult and pediatric patients with atopic dermatitis (AD), assessing its impact on skin condition and mood regulation by investigating serum concentrations of serotonin and kynurenine pathway metabolites. METHODS: 20 patients (age 9-45) with moderate and severe AD were included in the study. Treatment consisted of 10 irradiations with Full Body Blue device (453 nm). Serum concentrations of serotonin, quinolinic acid, kynurenic acid, tryptophan, and kynurenine were measured before and after irradiations. RESULTS: After 10 sessions of full blue light therapy (453 nm) statistically significant improvements were observed in Eczema Area Severity Index (EASI 13.16 vs. 8.65; p = 0.00016), SCORing Atopic Dermatitis (SCORAD 44.99 vs. 23.73; p < 0.00001), Visual Analogue Scale (VAS 6.53 vs. 3.95; p = 0.00251), 10-item pruritus severity scale (13.32 vs. 7.05; p < 0.00001). Moreover, statistically significant decrease in Dermatology Life Quality Index (DLQI) was noted (14.37 vs. 7.42; p = 0.00351). Additionally, increase in the serum concentration of serotonin was observed after completing 10 irradiation sessions (median 139.77 mg/ml vs. 274.92 mg/ml; p < 0.00001). CONCLUSION: Blue light may be a promising and safe treatment in patients with AD. It might also positively influence mood. Further investigations are needed to confirm those findings. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT06516783.

Prevalence, severity, and risk factors of eczema among young children and adolescents in Saudi Arabia: A national cross-sectional study, 2019.

Background: Eczema is a common inflammatory skin disease with a significant global health burden. Eczema has a significant impact on quality of life. Objective: We aimed to estimate the prevalence, severity, and risk factors associated with eczema among schoolchildren in Saudi Arabia. Methods: The standardized Global Asthma Network questionnaires and methodology were used to conduct a nationwide cross-sectional study across 20 regions in Saudi Arabia between March and April 2019. Data were collected from 137 primary schools and 140 intermediate schools by using a multistage stratified cluster sampling method. Results: The study included 3614 young children aged 6 to 7 years and 4068 adolescents aged 13 to 14 years. Current eczema was prevalent among 4.5% of the children and 5.1% of the adolescents. Severe eczema was reported in 0.8% and 0.9% of the young children and adolescents, respectively. Several factors showed significant association with eczema. Among the children, eczema was linked positively to having a history of chest infections and wheezing in early life, as well as to ever attending day care and current exposure to cats. Among the adolescents, the main potential risk factors included paracetamol use in the previous year, adherence to a lifestyle of vigorous physical activity, and current exposure to cats. Conversely, high consumption of nuts was found to be negatively associated with eczema. Conclusion: The prevalence of eczema in schoolchildren in Saudi Arabia is lower than the global average but within the average range for the Eastern Mediterranean region. Further studies in Saudi Arabia should be conducted to identify variation among different regions.

Povidone-Iodine Induced Allergic Contact Dermatitis in a 10-Year-Old Girl: A Case Report.

We present a case of iodine-induced allergic contact dermatitis in a 10-year-old child. The child had a superficial wound on the left knee from an injury and was treated with daily applications of povidone-iodine (PVP-I) ointment for three to four days. The child subsequently developed a worsening skin lesion that increased from an initial 2 cm to 10 cm, spreading over the upper part of the leg, accompanied by pain and scanty discharge. Referred to the dermatology department, the dermatologist diagnosed iodine-induced allergic contact dermatitis based on the clinical presentation and the absence of other oral or topical medications, as well as no history of allergy to any substances or medications. Discontinuation of the suspected PVP-I ointment led to complete healing within 10 days with the use of only an emollient. This case underscores the importance of recognizing iodine allergy as a potential complication when used in wound care, particularly in pediatric patients.

Translation and cross-cultural adaptation of the Nordic Occupational Skin Symptoms Questionnaire to Brazilian Portuguese.

Introduction: Occupational skin diseases are a frequently self-reported condition in industrialized countries. However, there are few developed and standardized self-report instruments to screen the population at risk for occupational dermatological diseases. Objectives: Translation and cross-cultural adaptation of the long and short versions of The Nordic Occupational Skin Symptoms Questionnaire into Brazilian Portuguese. Methods: The process of translation and cross-cultural adaptation of the questionnaire was developed following the good practice recommendations of the International Society for Pharmacoeconomics and Outcomes Research. Results: After translation into Brazilian Portuguese, the first reconciled version of the questionnaire was evaluated in a first round of interviews with 28 individuals, including patients with dermatological disease and healthy people. In the first meeting of the study review group, changes were made to 43 questions (75.4%) (e.g., inclusion of definition of terms, reformulation of instructions, and changes to alternative words or synonyms). In the second meeting of the study review group, there were modifications in three questions, creation of the second consensus version in Brazilian Portuguese, and then the back-translation of this version. After the second round of cognitive interviews, which took place with 10 patients, we had the third review group meeting (no modification was made) and definition of the final version of the questionnaire. Conclusions: The short and long versions of the Nordic Occupational Skin Symptoms Questionnaire questionnaire are available in Brazilian Portuguese.

Introdução: As doenças ocupacionais de pele são uma condição frequentemente autorrelatada em países industrializados. No entanto, existem poucos instrumentos de autorrelato desenvolvidos e padronizados para triagem da população de risco para doenças ocupacionais de pele. Objetivos: Tradução e Adaptação Transcultural da versão longa e curta do Nordic Occupational Skin Symptoms Questionnaire para o português brasileiro. Métodos: O processo de tradução e adaptação transcultural do questionário foi desenvolvido seguindo as boas práticas recomendadas pela International Society for Pharmacoeconomics and Outcomes Research. Resultados: Após a tradução para o português brasileiro, a primeira versão conciliada do questionário foi avaliada em uma primeira rodada de entrevistas com 28 indivíduos entre pacientes com doença dermatológica e pessoas saudáveis. Na primeira reunião do grupo de revisão do estudo, foram feitas alterações em 43 questões (75,4%) (por exemplo, inclusão de definição de termos, reformulação de instruções e alteração para palavras alternativas ou sinônimos). Na segunda reunião do grupo de revisão do estudo, houve modificações em três questões, criação da segunda versão de consenso em português brasileiro e, posteriormente, a retrotradução desta versão. Após a segunda rodada de entrevistas cognitivas, que ocorreram com 10 pacientes, tivemos a terceira reunião do grupo de revisão (não houve modificação) e definição da versão final do questionário. Conclusões: As versões curta e longa do questionário Nordic Occupational Skin Symptoms Questionnaire estão disponíveis em português brasileiro.

Targeted therapy for immune mediated skin diseases. What should a dermatologist know?

Abstract Background Molecularly targeted therapies, such as monoclonal antibodies (mAbs) and Janus Kinase inhibitors (JAKis), have emerged as essential tools in the treatment of dermatological diseases. These therapies modulate the immune system through specific signaling pathways, providing effective alternatives to traditional systemic immunosuppressive agents. This review aims to provide an updated summary of targeted immune therapies for inflammatory skin diseases, considering their pathophysiology, efficacy, dosage, and safety profiles. Methods The review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. A systematic search was conducted on PubMed over the past 10 years, focusing on randomized clinical trials, case reports, and case series related to targeted immune therapies in dermatology. Eligibility criteria were applied, and data were extracted from each study, including citation data, study design, and results. Results We identified 1360 non-duplicate articles with the initial search strategy. Title and abstract review excluded 1150, while a full-text review excluded an additional 50 articles. The review included 143 studies published between 2012 and 2022, highlighting 39 drugs currently under investigation or in use for managing inflammatory skin diseases. Study limitations The heterogeneity of summarized information limits this review. Some recommendations originated from data from clinical trials, while others relied on retrospective analyses and small case series. Recommendations will likely be updated as new results emerge. Conclusion Targeted therapies have revolutionized the treatment of chronic skin diseases, offering new options for patients unresponsive to standard treatments. Paradoxical reactions are rarely observed. Further studies are needed to fully understand the mechanisms and nature of these therapies. Overall, targeted immune therapies in dermatology represent a promising development, significantly improving the quality of life for patients with chronic inflammatory skin diseases.

Are behavioral interventions a better choice for atopic dermatitis patients? A meta-analysis of 6 randomized controlled trials

Abstract Background The treatment for atopic dermatitis (AD) has been the focus of clinical research, and behavioral intervention is considered an indispensable treatment method. To our knowledge, no relevant meta-analysis has evaluated the effects of behavioral interventions on atopic dermatitis. Objectives To evaluate the effects of behavioral interventions on atopic dermatitis. Methods The authors searched PubMed, EMBASE, and Cochrane CENTRAL to retrieve relevant RCTs (up to Feb 2022). The search strategy involved a combination of related keywords. The Cochrane Q and I2 statistics were used to assess heterogeneity. Results Six RCTs involving seven reports with 246 patients were included. The results suggested that behavioral interventions could relieve eczema severity (correlation coefficient [r = −0.39]; p < 0.001) and scratching severity significantly (r = −0.19; p = 0.017), while not affect itching intensity (r = −0.02; p = 0.840). A sensitivity analysis confirmed the robustness of the results. Study limitations An important limitation of this study was the insufficient number of RCTs and the limited sample size. In addition, the study lacked a control group receiving a type of intervention other than the experimental protocol. Another limitation was the short duration of follow-up. Conclusions This study suggests that behavioral interventions could be effective in treating atopic dermatitis by reducing eczema and scratching severity. Additionally, habit-reversal behavioral therapy may be more effective for treating atopic dermatitis.

Effects of eczema calming lotion on the stratum corneum in atopic dermatitis: Corneodesmosin and intercellular lipid lamellae.

OBJECTIVE: Atopic dermatitis (AD) is characterized by compositional and structural changes to the skin at lesional sites. Alteration to the levels and organization of both protein and lipid components are associated with disease status and lead to impaired barrier and hydration. Corneodesmosin (CDSN) and the arrangement and length of the intercellular lipid lamellae (ICLL) are altered in disrupted skin states. The aim of this research was to profile the distribution of CDSN and the ICLL in the stratum corneum (SC) at lesional and non-lesional sites in AD-prone skin and to investigate the impact of an eczema calming lotion containing petroleum jelly, fatty acids, and colloidal oatmeal. METHODS: An IRB-approved study was conducted with participants with active AD. From a small subset of participants, tape strips were collected from lesional and non-lesional sites on the arm, prior to and after twice daily application, over 4 weeks of an eczema calming lotion containing petroleum jelly, fatty acids, and colloidal oatmeal. Fluorescent antibody staining was used to investigate the distribution of CDSN. Transmission electron microscopy (TEM) was used to characterize the ICLL. RESULTS: The distribution/coverage of CDSN was similar between lesional and non-lesional sites at baseline; application of the lotion resulted in a more defined honeycomb/peripheral distribution. Normalized ICLL (nICLL) was lower in baseline samples from lesional sites relative to non-lesional sites. Application of the lotion increased this parameter by the end of the study at all sites. CONCLUSION: The eczema calming lotion containing petroleum jelly, fatty acids and colloidal oatmeal provided changes in corneodesmosomal proteins distribution and ICLL, consistent with improvements in corneocyte maturation and improved barrier function in the skin of individuals with atopic dermatitis.

OBJECTIF: La dermatite atopique (DA) est caractérisée par des modifications de la composition et de la structure de la peau au niveau des sites lésionnels. L'altération des taux et de l'organisation des composants protéiques et lipidiques est associée au statut de la maladie, et entraîne une altération de la barrière et de l'hydratation. La cornéodesmosine (CDSN), et la disposition et la longueur des lamelles lipidiques intercellulaires (LLIC) sont altérées dans les états cutanés perturbés. L'objectif de cette étude était d'établir le profil de la distribution de la CDSN et des LLIC dans la couche cornée (CC) au niveau des sites lésionnels et non lésionnels dans la peau sujette à la DA, et d'étudier l'impact d'une lotion apaisante contre l'eczéma contenant de la vaseline, des acides gras et de l'avoine colloïdale. MÉTHODES: Une étude approuvée par un CPP a été menée auprès de participants atteints de DA active. Dans un petit sous­ensemble de participants, des bandes adhésives ont été prélevées sur des sites lésionnels et non lésionnels du bras, avant et après l'application deux fois par jour pendant 4 semaines d'une lotion apaisante contre l'eczéma contenant de la vaseline, des acides gras et de l'avoine colloïdale. Une coloration par anticorps fluorescents a été utilisée pour étudier la distribution de la CDSN. La microscopie électronique en transmission (MET) a été utilisée pour caractériser les LLIC. RÉSULTATS: La distribution/couverture de la CDSN était similaire entre les sites lésionnels et non lésionnels à l'entrée dans l'étude; l'application de la lotion a entraîné une distribution en nid d'abeille/périphérique plus définie. Le taux normalisé de LLIC (LLICn) était plus faible dans les échantillons prélevés à l'entrée dans l'étude au niveau des sites lésionnels par rapport aux sites non lésionnels. L'application de la lotion a augmenté ce paramètre à la fin de l'étude pour tous les sites. CONCLUSIONS: La lotion apaisante contre l'eczéma contenant de la vaseline, des acides gras et de l'avoine colloïdale a entraîné des changements dans la distribution des protéines cornéodesmosomales et des LLIC, ce qui correspond à des améliorations de la maturation des cornéocytes et de la fonction de barrière de la peau des personnes atteintes de dermatite atopique.

Examining the Efficacy of Five Lactobacillus Species in Treating and Preventing Atopic Dermatitis: A Systemic Literature Review.

Probiotics have garnered increasing attention, particularly within the realm of atopic dermatitis (AD). Although classified as dietary supplements by the Food and Drug Administration, probiotics are being explored for their potential to modify immune system responses and aid in disease recovery. This review aims to provide a current understanding of probiotics, specifically various lactobacilli strains, as a therapeutic option in preventing and treating AD. The concept of the gut-skin axis has gained substantial recognition, emphasizing the complex relationship between the gut microbiome and skin health. Dysfunctional gut barriers and metabolites produced by gut microorganisms can exert profound influences on skin conditions, including AD. Lactobacilli species are particularly noteworthy for their resilience and stability within the gastrointestinal tract, making these bacteria ideal candidates for probiotic supplementation. Various lactobacilli strains (Lactobacillus salivarius, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus reuteri, and Lactobacillus rhamnosus) were included in this study due to their current uses in mitigating AD symptomatology. This systemic review article aims to shed light on the potential of probiotics as a therapeutic approach for AD, highlighting their stellar safety profile and promising therapeutic efficacy. Given the compelling preliminary findings and the constraints associated with conventional treatments, probiotics, particularly lactobacilli strains, emerge as a considerable alternative or adjuvant option for individuals grappling with AD. Further exploration is imperative to establish probiotics as a promising therapeutic option, providing renewed hope for those seeking effective strategies for managing AD.

Real-life management of atopic dermatitis patients with an inadequate response to on-label use of dupilumab.

In patients with moderate to severe atopic dermatitis (AD) showing an inadequate response to dupilumab 300mg/2weeks, few real-life studies reported the response to alternative regimen maintaining dupilumab. To assess and analyze the response to an increased dose of dupilumab or its combination with cyclosporin A (CsA), methotrexate (MTX), or itraconazole (ITRA), all adult AD patients from 7 French University Hospitals were retrospectively included if they achieved an inadequate response to dupilumab 300mg/2weeks and were subsequently treated with an increased dose of dupilumab (300mg every 7 or 10 days), or a combination of dupilumab 300mg/2weeks with CsA, MTX or ITRA. The response after 3 months, along with epidemiological, clinical, and therapeutic baseline characteristics, were collected. Overall, 68.75% of the 48 included patients achieved an improved response, including 45.8% of complete response (CR). No strategy proved significantly better. Patients showing an initial no response never achieved a further CR versus 52.4% of patients with an initial partial response (p = 0.025). Digestive intolerance and tachycardia led to MTX and ITRA discontinuation in 3 patients. Increasing the dose of dupilumab or combining it with CsA, MTX, or ITRA could be alternative and safe options, to be evaluated in further medico-economic studies.

Higher prevalence of dupilumab-induced ocular adverse events in atopic dermatitis compared to asthma: A daily practice analysis.

BACKGROUND: Dupilumab has been shown to be an effective treatment in moderate-to-severe atopic dermatitis (AD) and severe asthma (SA). However, comparative real-world analyses of adverse events (AE), particularly dupilumab-associated ocular surface disease (DAOSD), are lacking. OBJECTIVE: This is the first real-world study to provide insight into the prevalence of AEs associated with dupilumab in AD compared with SA. Secondary objectives were to assess the prevalence, onset and therapeutic strategies of DAOSD and evaluate dupilumab discontinuation rates. METHODS: Data from two daily practice registries including AD and SA patients receiving dupilumab treatment were analyzed. Adverse events, including DAOSD, were evaluated. RESULTS: In total, 322 AD and 148 SA patients were included. Headaches (23.6%), injection site reactions (10.1%), and influenza-like symptoms (13.5%) were more prevalent in SA patients. Interestingly, ocular AEs were significantly more prevalent in AD patients (62.1%, p < 0.001), including conjunctivitis (17.1%, p = 0.004). 88% AD and 47% SA patients with ocular AEs received one or more ophthalmic treatment(s). Additionally, 20% of AD and 17.6% of SA patients discontinued dupilumab treatment due to ocular AEs, while only 65% of these AD and none of these SA patients were referred to an ophthalmologist. CONCLUSION: The higher incidence of DAOSD in AD patients compared with SA patients in this real-world study highlights the importance of physician awareness, especially when prescribing dupilumab to AD patients. Conversely, the findings of this study help alleviate potential concerns about ocular AEs in patients with SA who do not have comorbid AD. Furthermore, the effective management of most ocular AEs with ophthalmic treatments suggests favorable tolerability of dupilumab in daily practice, and multidisciplinary collaboration is essential to proactively manage ocular AEs before discontinuing dupilumab.

Hidden formaldehyde in cosmetic products.

BACKGROUND: Formaldehyde is a common cause of contact allergy. Hidden formaldehyde, that is, formaldehyde in products without formaldehyde releasers, has previously been detected in cosmetic products. OBJECTIVES: The objective of this study was to investigate the content and causes of hidden formaldehyde in leave-on cosmetic products. METHODS: The formaldehyde release from 142 cosmetic products, primarily creams, was analysed using the chromotropic acid (CA) method. The study included 130 products with no formaldehyde releasers on the ingredient list and 12 products with formaldehyde releasers. Products without formaldehyde releasers positive to CA, that is, with formaldehyde ≥2.5 ppm, were additionally analysed using high-performance liquid chromatography (HPLC). Formaldehyde release from selected raw materials and packaging were also investigated. RESULTS: Hidden formaldehyde was found in 23 of the 130 products (18%) without formaldehyde releasers on the ingredient list. The average formaldehyde content was 105 ppm (range: 0.5-507 ppm) in products with hidden formaldehyde and 355 ppm (range: 75-637 ppm) in eight products with formaldehyde releasers, selected for HPLC analysis. Impurities of formaldehyde in dihydroxyacetone may be a cause of hidden formaldehyde in self-tanners. No clear pattern was found for the other products with hidden formaldehyde. CONCLUSIONS: Changes in regulation are needed to prevent allergic contact dermatitis from hidden formaldehyde in cosmetic products.

The potential of Bruton's tyrosine kinase (BTK) inhibitors in the pharmacotherapeutic management of immune and dermatological disease.

INTRODUCTION: The review article explores the evolving role of Bruton's tyrosine kinase (BTK) inhibitors in immune-mediated dermatological conditions, addressing significant gaps in current treatment approaches. AREAS COVERED: The review comprehensively discusses the mechanisms of action of BTK inhibitors, including irreversible and reversible inhibitors. Clinical applications of BTK inhibitors in dermatological diseases such as pemphigus, chronic spontaneous urticaria (CSU), hidradenitis suppurativa (HS), systemic lupus erythematosus (SLE), and atopic dermatitis are explored, highlighting recent advancements and ongoing clinical trials. Potential advantages of BTK inhibitors over existing therapies and challenges in translating preclinical findings to clinical outcomes are discussed. EXPERT OPINION/COMMENTARY: BTK inhibitors represent a promising therapeutic avenue for immune-mediated dermatological conditions, offering oral administration, targeted pathway inhibition, and a favorable safety profile compared to biologic therapies. Ongoing research and clinical trials hold the potential to address unmet needs and reshape the therapeutic landscape in dermatology.

Our manuscript explores how a new class of medications called Bruton tyrosine kinase (BTK) inhibitors could revolutionize the treatment of skin conditions caused by the immune system. These conditions, like chronic spontaneous urticaria (CSU), pemphigus, and systemic lupus erythematosus (SLE), often lack effective treatments. BTK inhibitors work by targeting specific pathways in the immune system, offering hope for patients with these challenging conditions.We reviewed clinical trials and research studies to understand how BTK inhibitors could benefit patients. One significant advantage of BTK inhibitors is their ability to provide targeted therapy, meaning they can specifically block the faulty immune responses driving these conditions without affecting the entire immune system. This targeted approach could lead to fewer side effects compared to current treatments, such as corticosteroids or immunosuppressants, which can have widespread effects on the body.Overall, BTK inhibitors represent a promising new approach to treating immune-mediated skin conditions. With further research and development, they could offer safer and more effective alternatives to current treatments, improving the lives of patients worldwide.

Efficacy and Safety of Upadacitinib in Moderate-to-Severe Atopic Dermatitis: A Meta-Analysis.

Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disorder. Topical corticosteroids are the cornerstone of therapy in mild AD, whereas the JAK inhibitor upadacitinib is approved in the United States, Europe, and other countries for treating moderate-severe AD in adults and children over 12 years old whose disease is not adequately controlled with other systemic drugs, including biologics. The objective of this meta-analysis was to assess the overall efficacy and safety of upadacitinib in moderate to severe AD. All randomized controlled trials (RCTs) evaluating the efficacy and safety of upadacitinib in moderate to severe AD were included in the meta-analysis. The pooled analysis revealed a significant proportion of patients achieving Eczema Area and Severity Index-75 (EASI 75) (R.R. = 3.86; 95% CI = 3.12 to 4.78, p < 0.00001), EASI 100 (R.R. = 13.09; 95% CI = 7.40 to 23.17, p < 0.00001), Worst Pruritus Numerical Rating Score (WP-NRS) response (R.R. = 4.44; 95% CI = 3.72 to 5.29, p< 0.00001), and validated Investigator's Global Assessment (v-IGA) (RR = 5.96; 95% CI = 4.79 to 7.41, p < 0. 00001) in the upadacitinib arm compared to the placebo arm. Moreover, the pooled analysis also suggested that treatment-emergent adverse events (TAEs) were relatively higher with upadacitinib than with placebo, but were mild and easily manageable (R.R. = 1.15; 95% CI = 1.09 to 1.23, p<0.00001). This meta-analysis showed that upadacitinib had a significant beneficial effect and tolerable adverse effect profile in patients with moderate and severe AD. Dose regimens of 15 mg and 30 mg seemed to have similar benefits. However, further trials are needed to assess long-term efficacy and safety profile.

Phase 1 Safety and Pharmacokinetics Study of TAVO101, an Anti-Human Thymic Stromal Lymphopoietin Antibody for the Treatment of Allergic Inflammatory Conditions.

TAVO101 is a humanized anti-human thymic stromal lymphopoietin (TSLP) monoclonal antibody under clinical development for the treatment of atopic dermatitis (AD) and other allergic inflammatory conditions. The crystallizable fragment region of the antibody was engineered for half-life extension and attenuated effector functions. This Phase 1, double-blinded, randomized, placebo-controlled study assessed the safety, tolerability, pharmacokinetics, and immunogenicity of TAVO101 in healthy adult subjects in seven ascending dose cohorts. Subjects received a single intravenous administration of TAVO101 or placebo with a 195-day follow-up. TAVO101 was safe and well tolerated. The incidences and severities of treatment-emergent adverse events were mostly mild and comparable between the active and placebo groups, with no trends of dose relationship. There were no severe adverse events, deaths, or treatment-related withdrawals. TAVO101 exhibited a linear pharmacokinetic profile, low clearance, and a median elimination half-life of 67 days in healthy subjects. All TAVO101-treated subjects tested negative for anti-drug antibodies. To support development in AD, TAVO101 was studied in an oxazolone-induced AD model in hTSLP transgenic mice and demonstrated efficacy. This long-acting anti-TSLP antibody has the potential for stronger and sustained allergic inflammatory disease control. The results from this study warranted further clinical development of TAVO101 in patients.

Skin microdialysis detects distinct immunological patterns in chronic inflammatory skin diseases.

BACKGROUND: Insight into the pathophysiology of inflammatory skin diseases, especially at the proteomic level, is severely hampered by the lack of adequate in situ data. OBJECTIVE: Characterize lesional and nonlesional skin of inflammatory skin diseases using skin microdialysis. METHODS: Skin microdialysis samples from patients with atopic dermatitis (AD, n=6), psoriasis vulgaris (PSO, n=7) or prurigo nodularis (PN, n=6), as well as healthy controls (n=7) were subjected to proteomics and multiplex cytokine analysis. Single-cell RNA sequencing of skin biopsy specimens was used to identify the cellular origin of cytokines. RESULTS: Among the top 20 enriched GO annotations, NAD metabolic process, regulation of secretion by cell, and pyruvate metabolic process were elevated in microdialysates from lesional AD skin compared with both nonlesional skin and controls. The top 20 enriched KEGG pathways in these three groups overlapped almost completely. In contrast, nonlesional skin from patients with PSO or PN and control skin showed no overlap with lesional skin in this KEGG pathway analysis. Lesional skin from patients with PSO, but not AD or PN, showed significantly elevated protein levels of MCP-1 compared to nonlesional skin. IL-8 was elevated in lesional vs nonlesional AD and PSO skin, whereas IL-12p40 and IL-22 were higher only in lesional PSO skin. Integrated single-cell RNA-seq data revealed identical cellular sources of these cytokines in AD, PSO and PN. CONCLUSION: Based on microdialysate, proteomic data of lesional PSO and PN skin, but not lesional AD skin, differed significantly from those of nonlesional skin. IL-8, IL-22, MCP-1 and IL-12p40 might be suitable markers for minimally invasive molecular profiling.

Pharmacokinetics, Safety, Tolerability, and Exploratory Efficacy of Upadacitinib in Children with Severe Atopic Dermatitis.

PURPOSE: This study aims to characterize the pharmacokinetics, safety, tolerability, and exploratory efficacy of upadacitinib, an oral Janus kinase inhibitor approved for treating moderate to severe atopic dermatitis (AD) in adults and adolescents, in children with severe AD. METHODS: In an open-label, multiple-dose, Phase 1 study, pediatric patients with severe AD from two age groups (2 to <6 years and 6 to <12 years) received bodyweight-based dosing regimens of upadacitinib using either twice-daily immediate-release (IR) oral solution or once-daily extended-release (ER) tablets. A pharmacokinetic assessment was conducted on Day 7 of the study, which was followed by a long-term safety and exploratory efficacy evaluation for up to 108 weeks. The results reported here are based on an interim analysis when the study had completed enrollment and pharmacokinetic assessment. FINDINGS: A total of 35 patients were enrolled and received upadacitinib. The maximum upadacitinib plasma concentration was attained within a median time of 0.5 to 2 hours and 2 to 2.5 hours for the IR oral solution and ER tablet formulations, respectively. Upadacitinib functional half-life was generally shorter with IR oral solution relative to ER tablets. Upadacitinib apparent oral clearance decreased with decreasing body weight in the pediatric patients enrolled in this study. Upadacitinib was generally safe and well tolerated. The most common (≥3 patients) adverse events were upper respiratory tract infection, COVID-19 infection, headache, abdominal discomfort, vomiting, asthma, and cough. No new safety risks were identified compared to the known safety profile for upadacitinib in adults and adolescents. In the 30 patients with available exploratory efficacy data at Week 12, 36.7% achieved validated Investigator's Global Assessment scale for AD score of 0 or 1 (Validated Investigator Global Assessment for AD 0/1), and 70.0% had Eczema Area and Severity Index (EASI) improvement of at least 75% (EASI 75). IMPLICATIONS: The characterized pharmacokinetic profiles in this study, together with the observed safety and exploratory efficacy results, support further investigation of the current upadacitinib dosing regimen in future confirmatory Phase 3 clinical trials in children with AD. CLINICAL TRIAL NUMBER: NCT03646604, registered 2018-08-23.

Immunofluorescence findings in a reactivating lichenoid photoallergic chronic dermatitis (actinic reticuloid).

BACKGROUND: Chronic photosensitivity dermatitis (CPD) (also named actinic reticuloid) is an unusual disease classically referred often in elderly men. Affected patients have severely itchy, thickened dry skin in areas exposed to the sun throughout the years. METHOD: A Caucasian female patient who worked most of her life outside who had "chronic dermatitis" in her neck started planting chrysanthemum in her garden on a sunny day. Later, she presented edema, erythema, papules, and a few vesicles in her neck with severe pruritus. STUDIES: A skin biopsy revealed the diagnosis of CPD, along with positive testing for ultraviolet B (UVB), minimal erythema doses (MED) for UVB (MEDB) UVA (MEDA) and PhotoPath. RESULTS: Direct immunofluorescence (DIF) stains using anti-human antibodies against fibrinogen, albumin, IgG, IgM, lambda, kappa, and C3c and C1q were positive at the base membrane area of the dermal epidermal junction, in the papillary dermis, as well as the neurovascular bundles in all the dermis and the extracellular matrix, especially those under the blisters. CONCLUSION: With this case, we suggest not forgetting the importance of using DIF in reactivated CPD cases in addition to the photo patch testing.